A variety of conditions and situations present the problem of undesirable amounts of saliva in the mouth of an individual. Classically, “sialorrhea” has been defined as “excess production of saliva, or increased retention of saliva in the mouth” or “saliva beyond the margin of the lip”, i.e., drooling, although the term sialorrhea has sometimes more loosely been used to describe “excessive saliva secretion”. Sialorrhea, i.e., drooling, is a well known, but often not discussed, condition that affects patients with various neurological diseases and such conditions as Parkinson's disease, Lewy body disease, cerebral palsy, amyotrophic lateral sclerosis (ALS, otherwise known as Lou Gehrig's disease), muscular dystrophy and multiple sclerosis, as well as oropharyngeal carcinomas. Sialorrhea also affects individuals with mental and developmental disabilities, those who have sustained various brain injuries, and individuals who have had a stroke. Sialorrhea may also occur as the result of neuromuscular dysfunction, sensory dysfunction, motor dysfunction, parkinsonism, pseudobulbar palsy, bulbar palsy, multiple system atrophy, corticobasal degeneration, motor neuron diseases, and neurodegenerative diseases. Several other situations predispose the development of sialorrhea due to the imperfect control of orofacial, head, and neck musculature, as is commonly found, e.g., in patients with cerebrovascular accidents, head injuries, severe dental malocclusion, and mental retardation. Adverse drug reactions involving tranquilizers, anticonvulsants, and anticholinesterases (e.g., clozapine and other drugs used to treat schizophrenia, and remoxipride) can also aggravate sialorrhea by causing hypersecretion of saliva. Sialorrhea affects over 3 million people annually. A recent review of the etiology and management of the problem of drooling appears in Meningaud et al., Oral Surg. Oral Med. Oral Pathol. Oral Radiol. Endod., 101: 48-57 (2006).
Depending on its degree, drooling can result in social and medical disability, impaired speech, or serious feeding difficulties. Unable to manage their oral secretions, affected persons are at increased risk of aspiration pneumonia, skin maceration, and infection. Care may be compromised since the frequent suctioning and cleaning that are required to maintain proper hygiene can become very burdensome.
There are also a variety of situations in which it is desirable to temporarily inhibit or reduce saliva production in otherwise healthy individuals. For example, it is often useful or even necessary to maintain an adequately dry oral field to perform various dental, orthodontic, periodontal, and oral surgical procedures. For example, it is very important to maintain a dry oral field during many dental procedures, including cementation and bonding procedures, amalgam and composite restorations, the applications of sealants, and impressions during restoration of both anterior and posterior teeth. The increasing reliance of modern dentistry on adhesive materials has renewed the interest in means to maintain a dry field. Undesired saliva accumulation and drooling during such procedures has largely been addressed by employing one or more objects or mechanical devices that must be inserted into the mouth of a patient, e.g., suction devices, cotton rolls, and rubber dams. Such objects and devices can be cumbersome for both patient and the attending oral healthcare professional, interfere with the use of other tools employed in a procedure, invoke a gag response in the patient, and generally contribute to patient distress. The oral healthcare profession is continually seeking means and methods that will contribute to decreasing both a patient's experience as well as perception of distress associated with various dental and other oral healthcare procedures. Clearly, means and methods to produce an adequately dry oral field in a patient's mouth that also eliminate the necessity for using various mechanical objects as mentioned above would be highly desirable and would likely enhance patient acceptance of various dental, orthodontic, periodontal, and oral surgical procedures.
Saliva is produced by both the major and minor salivary glands. There are three pairs of major salivary glands: the parotid, submandibular, and sublingual glands. These glands produce from 1-1.5 liters of saliva daily in a circadian rhythm: in the resting state 70% of the saliva is from the submandibular glands, 25% is from the parotid glands, and 5% is from the sublingual glands. Minor salivary glands located on the palate, buccal mucosa, and tongue produce modest amounts of saliva. The secretory innervation of the salivary glands is primarily under the control of the parasympathetic nervous system. Stimulation of the parasympathetic system causes profuse secretion of saliva. The resting secretory rate may increase by 5 to 10-fold upon stimulation (olfactory, tactile, and gustatory).
Saliva is crucial for normal hygiene and serves important digestive, immunological, and protective functions. The goal in treating drooling is to reduce drooling but maintain a moist, healthy oral cavity. To eliminate drooling risks the significant complication of xerostomia (dry mouth). Over the last few years, efforts have been undertaken to develop treatments for sialorrhea that also address the dry mouth complication as well. Available therapies for treating sialorrhea include a variety of surgical procedures, radiation therapy, absorption devices, the use of certain drugs, and speech and behavioral therapy. No single therapy has been documented to resolve sialorrhea satisfactorily in all patients.
Surgical management of sialorrhea includes re-routing the parotid or submandibular ducts, excision of the submandibular glands, or transection of the nerves innervating the parotid gland or submandibular gland. Selection of the procedure seems to be largely a physician/patient preference issue that involves balancing the increased morbidity of the gland excision or duct relocation procedures against the threat of recurrence and the loss of taste associated with the nerve severing procedures.
Radiation therapy has been shown to produce glandular atrophy and decreases secretions; however, the dose required for atrophy may produce xerostomia, and the potential risk of secondary malignancy exists. In most cases, it seems inappropriate to substitute the dangers of radiation for the alleviation of drooling. Nevertheless, when drooling occurs in association with a terminal illness, use of radiotherapy may be warranted.
Recently, treatments for sialorrhea have included the use of commercial preparations of botulinum toxin A or B (e.g., Botox® botulinum toxin A preparation by Allergan, Inc.; Dysport® botulinum toxin A preparation by Ipsen Biopharm; Myobloc® botulinum toxin B preparation by Elan Pharmaceuticals) that can be injected directly, for example, into the parotid salivary glands. Several clinical studies have shown improvements. The toxin needs to be injected directly into the parotid and submandibular glands in a procedure that requires a skilled physician under imaging support to locate the glands to be treated in order to avoid puncturing a nerve or a major blood vessel. Studies claim that the effects last for a few months at best. Typically, saliva production is decreased by about 50-60% in about half the patients. While injections of botulinum toxin could be an option for a small portion of patients, the procedure is expensive, invasive, and not free of risk for serious complications.
Research into medicinal therapy has focused on the use of systemic anti-cholinergic drugs, such as atropine, scopolamine, and glycopyrrolate, which have been shown to reduce the production of saliva. These drugs do not prevent the release of acetylcholine but antagonize the effect of this neurotransmitter on the effector cells. This action results in drying of the mouth through reduction of salivary gland secretions. However, current therapeutic doses and the route of administration of these drugs usually result in unacceptable side effects such as constipation, urinary retention, blurred vision, and restlessness that greatly limit the potential for widespread use of such therapies. Glycopyrrolate is an anti-cholinergic drug approved to treat ulcers. It has been shown to be effective in the control of excessive sialorrhea in children with developmental disabilities, however approximately 20% of the treated individuals experienced substantial adverse systemic side effects requiring discontinuation of medication (see, e.g., Mier et al., Arch. Pediatr. Adolesc. Med., 154: 1214-1218 (2000)). Others studies employing systemic administration of glycopyrrolate have reported behavioral changes.
The use of atropine sulfate tablets (e.g., Sal-Tropin® atropine sulfate tablets, Hope Pharmaceuticals) to treat sialorrhea has been reported by Sherman (Sherman C. R, Gen. Dent., 47: 56-60 (1999)). Side effects include mild stimulation to the central nervous system at low doses, while larger doses can cause mental disturbances and depression. Death from atropine poisoning, though rare, is usually due to paralysis of the medullary centers. Other reports detail similar consequences when using atropine (see, e.g., Sharma et al., Ann. Pharmacother., 38(9): 1538 (2004); Comley et al., Austr. N. Z. J. Psychiatry, 34(6): 1033-1034 (2000); Antonello et al. (J. Psychiatry Neurosci., 24(3): 250 (1999)).
Other pharmacological treatments have been proposed to treat sialorrhea including the use of amitriptyline (a tricyclic antidepressant) and clonidine (an alpha-2-selective adrenergic agonist). However, due to the lack of efficacy and/or a high incidence of side effects, these drugs have not been approved for the treatment of sialorrhea.
One of the persistent problems in treating sialorrhea is the lack of local therapy. The above treatments were administered systemically and had many adverse reactions. For example, many sialorrhea patients are not deemed appropriate for systemic medications due to concomitant medical illness.
A pilot study with seven patients conducted by Hyson et al. (Mov. Disord., 17(6): 1318-1320 (2002)) showed that sublingually administered atropine was effective in achieving a decrease in salivation in patients with Parkinson's disease. No effect was noted after 30 minutes, and results were first observed three hours after the initial treatment. A 32% decrease was observed in the volume of saliva.
Freudenreich reported a study of patients who used sublingual ipratropium (a bronchodilator) for clozapine-induced sialorrhea (Freudenreich, J. Clin. Psychopharmacol., 24(1): 98-100 (2004)). Patients were initially administered two doses of 0.03% ipratropium sprayed sublingually at bedtime. Dosing was subsequently increased to 3 times daily. Of the nine patients who tried sublingual ipratropium, most had a partial yet clinically meaningful response. Typically, the effect of the spray wore off after a few hours (range 2-8 hours). Intranasal application has also been reported to be effective for clozapine-induced sialorrhea (Calderon et al., Int. Clin. Psychopharmacol., 15: 49-52 (2000)).
Ipratropium is structurally related to atropine but differs in one significant distinguishing feature in that ipratropium is a charged quaternary amine whereas atropine is a neutral tertiary amine. Typical quaternary amine anti-cholinergic agents include ipratropium, glycopyrrolate, methylatropine, and homatropine methylbromide. Quaternary ammonium compounds are less lipid-soluble than tertiary amines, their gastrointestinal adsorption is poor, and they do not readily pass the blood-brain barrier or conjunctiva. The charge of quaternary ammonium compounds presents a barrier to crossing membranes. Tertiary amine anti-cholinergic agents include atropine, hyoscyamine, scopolamine, hyoscine, eucatropine, homatropine, benzhexol, apoatropine, tropicamide, and cyclopentolate. A useful description of various anti-cholinergic drugs (“antimuscarinics”) can be found in The Complete Drug References 34th edition, (The Royal Pharmaceutical Society of Great Britain, London, 2004).
None of the above-mentioned investigators optimized the dose and the dosage-form of the various drugs in order to target decreased sialorrhea. All of the investigators used a selected drug in its current, commercially available form as intended for treating an unrelated indication. As a result, some treatments required multiple administrations over a long period (up to a few days) in order for an effect to be noticed. Moreover, in addition to a long delay in producing an outcome, the effect of the drugs persisted longer than needed. The use of these drugs also produce various adverse, systemic effects such as blurred vision, photophobia, fast heart rate (tachycardia), and anhidrosis producing heat intolerance or impaired temperature regulation. Hyson and Freudenreich stated that the unwanted side effects noted in their respective studies were related to swallowing the liquids and causing systemic effects or, e.g., inadvertent contact of ipratropium with the eyes.
Furthermore, the results in the above-mentioned studies were limited by the methodology of the assessment that relied on patient self-report as determined by retrospective chart review. Placebo-controlled trials with the use of instrumentation to measure salivary flow will be needed to establish efficacy.
The problem with current systemic anti-cholinergic agents is that they take a relatively long time to take effect (i.e., hours), nerves throughout the body are affected, and patients are exposed to chronic 24-hour doses. Currently there is no completely safe therapy to resolve sialorrhea satisfactorily in all patients without significant side effects.
Clearly the need remains for an effective, easily administered treatment for sialorrhea and other situations where it is desirable to control or temporarily decrease saliva production.